Control of IGF-I levels with titrated dosing of lanreotide Autogel over 48 weeks in patients with acromegaly

Philippe Chanson, Françoise Borson-Chazot, Jean-Marc Kuhn, Joëlle Blumberg, Pascal Maisonobe, Brigitte Delemer, Lanreotide Acromegaly Study Group, F Archambeaud, S Arlot, J Bringer, P Caron, B Estour, Y Lorcy, J Mahoudeau, V Rohmer, J L Sadoul, J L Schlienger, P Roger, B Verges, R Gaillard, Philippe Chanson, Françoise Borson-Chazot, Jean-Marc Kuhn, Joëlle Blumberg, Pascal Maisonobe, Brigitte Delemer, Lanreotide Acromegaly Study Group, F Archambeaud, S Arlot, J Bringer, P Caron, B Estour, Y Lorcy, J Mahoudeau, V Rohmer, J L Sadoul, J L Schlienger, P Roger, B Verges, R Gaillard

Abstract

Background: An essential criterion for control of acromegaly is normalization of IGF-I levels. Somatostatin analogues act to suppress IGF-I and GH levels.

Objective: To assess the efficacy and safety of 48 weeks titrated dosing of lanreotide Autogel.

Design: Open-label, multicentre, phase III, 48-week trial.

Methods: Patients with active acromegaly (IGF-I levels > 1.3 times upper limit of age-adjusted normal range) were recruited. Twelve injections of lanreotide Autogel were given at 28-day intervals: during the 16-week fixed-dose phase, patients received 90 mg; in the 32-week dose-titration phase, patients received 60, 90 or 120 mg according to GH and IGF-I levels. Intention-to-treat analysis was performed to determine the proportion of patients with normalized age-adjusted IGF-I levels at study end. Secondary evaluations included GH levels, clinical acromegaly signs and safety.

Results: Fifty-seven of 63 patients completed the study. Lanreotide Autogel resulted in normalized age-adjusted IGF-I levels in 27 patients (43%, 95% CI 31-55). Mean GH levels decreased from 6.2 to 1.5 microg/l at study end, with 53 of 62 patients (85%) having GH levels < or = 2.5 microg/l (95% CI 76.7-94.3) and 28 of 62 patients (45%) with levels < 1 microg/l (95% CI 32.8-57.6). Twenty-four (38%) had both normal IGF-I levels and GH levels < or = 2.5 microg/l. Acromegaly symptoms reduced significantly in most patients throughout the study. The most common adverse events were gastrointestinal, as expected for somatostatin analogues.

Conclusions: Using IGF-I as primary end-point, 48 weeks lanreotide Autogel treatment, titrated for optimal hormonal control, controlled IGF-I and GH levels effectively, reduced acromegaly symptoms and was well tolerated.

Figures

Fig. 1
Fig. 1
Study design schema.
Fig. 2
Fig. 2
Reduction in mean (SE) levels of serum (a) IGF-I and (b) GH.
Fig. 3
Fig. 3
Proportion of patients with acromegaly symptoms by visit over duration of study.

References

    1. Melmed S, Casanueva F, Cavagnini F, Chanson P, Frohman LA, Gaillard R, Ghigo E, Ho K, Jaquet P, Kleinberg D, Lamberts S, Laws E, Lombardi G, Sheppard MC, Thorner M, Vance ML, Wass JA, Giustina A. Consensus statement: medical management of acromegaly. European Journal of Endocrinology. 2005;153:737–740.
    1. Colao A, Ferone D, Marzullo P, Lombardi G. Systemic complications of acromegaly: epidemiology, pathogenesis, and management. Endocrine Reviews. 2004;25:102–152.
    1. Holdaway IM, Rajasoorya C, Gamble GD. Factors influencing mortality in acromegaly. Journal of Clinical Endocrinology and Metabolism. 2004;89:667–674.
    1. Melmed S. Medical progress: acromegaly. New England Journal of Medicine. 2006;355:2558–2573.
    1. Caron P, Cogne M, Raingeard I, Bex-Bachellerie V, Kuhn JM. Effectiveness and tolerability of 3-year lanreotide Autogel treatment in patients with acromegaly. Clinical Endocrinology. 2006;64:209–214.
    1. Cozzi R, Montini M, Attanasio R, Albizzi M, Lasio G, Lodrini S, Doneda P, Cortesi L, Pagani G. Primary treatment of acromegaly with octreotide LAR: a long-term (up to nine years) prospective study of its efficacy in the control of disease activity and tumor shrinkage. Journal of Clinical Endocrinology and Metabolism. 2006;91:1397–1403.
    1. Freda PU. Somatostatin analogs in acromegaly. Journal of Clinical Endocrinology and Metabolism. 2002;87:3013–3018.
    1. Caron P, Beckers A, Cullen DR, Goth MI, Gutt B, Laurberg P, Pico AM, Valimaki M, Zgliczynski W. Efficacy of the new long-acting formulation of lanreotide (lanreotide Autogel) in the management of acromegaly. Journal of Clinical Endocrinology and Metabolism. 2002;87:99–104.
    1. Caron P, Bex M, Cullen DR, Feldt-Rasmussen U, Pico Alfonso AM, Pynka S, Racz K, Schopohl J, Tabarin A, Valimaki MJ. One-year follow-up of patients with acromegaly treated with fixed or titrated doses of lanreotide Autogel. Clinical Endocrinology. 2004;60:734–740.
    1. Ashwell SG, Bevan JS, Edwards OM, Harris MM, Holmes C, Middleton MA, James RA. The efficacy and safety of lanreotide Autogel in patients with acromegaly previously treated with octreotide LAR. European Journal of Endocrinology. 2004;150:473–480.
    1. Alexopoulou O, Abrams P, Verhelst J, Poppe K, Velkeniers B, Abs R, Maiter D. Efficacy and tolerability of lanreotide Autogel therapy in acromegalic patients previously treated with octreotide LAR. European Journal of Endocrinology. 2004;151:317–324.
    1. van Thiel SW, Romijn JA, Biermasz NR, Ballieux BE, Frolich M, Smit JW, Corssmit EP, Roelfsema F, Pereira AM. Octreotide long-acting repeatable and lanreotide Autogel are equally effective in controlling growth hormone secretion in acromegalic patients. European Journal of Endocrinology. 2004;150:489–495.
    1. Trainer PJ, Drake WM, Katznelson L, Freda PU, Herman-Bonert V, van der Lely AJ, Dimaraki EV, Stewart PM, Friend KE, Vance ML, Besser GM, Scarlett JA, Thorner MO, Parkinson C, Klibanski A, Powell JS, Barkan AL, Sheppard MC, Malsonado M, Rose DR, Clemmons DR, Johannsson G, Bengtsson BA, Stavrou S, Kleinberg DL, Cook DM, Phillips LS, Bidlingmaier M, Strasburger CJ, Hackett S, Zib K, Bennett WF, Davis RJ. Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant. New England Journal of Medicine. 2000;342:1171–1177.
    1. van der Lely AJ, Hutson RK, Trainer PJ, Besser GM, Barkan AL, Katznelson L, Klibanski A, Herman-Bonert V, Melmed S, Vance ML, Freda PU, Stewart PM, Friend KE, Clemmons DR, Johannsson G, Stavrou S, Cook DM, Phillips LS, Strasburger CJ, Hackett S, Zib KA, Davis RJ, Scarlett JA, Thorner MO. Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist. Lancet. 2001;358:1754–1759.
    1. Freda PU, Katznelson L, van der Lely AJ, Reyes CM, Zhao S, Rabinowitz D. Long-acting somatostatin analog therapy of acromegaly: a meta-analysis. Journal of Clinical Endocrinology and Metabolism. 2005;90:4465–4473.
    1. Giustina A, Barkan A, Casanueva FF, Cavagnini F, Frohman L, Ho K, Veldhuis J, Wass J, Von Werder K, Melmed S. Criteria for cure of acromegaly: a consensus statement. Journal of Clinical Endocrinology and Metabolism. 2000;85:526–529.
    1. Cozzi R, Attanasio R, Montini M, Pagani G, Lasio G, Lodrini S, Barausse M, Albizzi M, Dallabonzana D, Pedroncelli AM. Four-year treatment with octreotide-long-acting repeatable in 110 acromegalic patients: predictive value of short-term results? Journal of Clinical Endocrinology and Metabolism. 2003;88:3090–3098.
    1. Freda PU, Nuruzzaman AT, Reyes CM, Sundeen RE, Post KD. Significance of ‘abnormal’ nadir growth hormone levels after oral glucose in postoperative patients with acromegaly in remission with normal insulin-like growth factor-I levels. Journal of Clinical Endocrinology and Metabolism. 2004;89:495–500.
    1. Jehle S, Reyes CM, Sundeen RE, Freda PU. Alternate-day administration of pegvisomant maintains normal serum insulin-like growth factor-I levels in patients with acromegaly. Journal of Clinical Endocrinology and Metabolism. 2005;90:1588–1593.
    1. Mukherjee A, Monson JP, Jonsson PJ, Trainer PJ, Shalet SM. Seeking the optimal target range for insulin-like growth factor I during the treatment of adult growth hormone disorders. Journal of Clinical Endocrinology and Metabolism. 2003;88:5865–5870.
    1. Puder JJ, Nilavar S, Post KD, Freda PU. Relationship between disease-related morbidity and biochemical markers of activity in patients with acromegaly. Journal of Clinical Endocrinology and Metabolism. 2005;90:1972–1978.
    1. Swearingen B, Barker FG, 2nd, Katznelson L, Biller BM, Grinspoon S, Klibanski A, Moayeri N, Black PM, Zervas NT. Long-term mortality after transsphenoidal surgery and adjunctive therapy for acromegaly. Journal of Clinical Endocrinology and Metabolism. 1998;83:3419–3426.
    1. Kauppinen-Makelin R, Sane T, Reunanen A, Valimaki MJ, Niskanen L, Markkanen H, Loyttyniemi E, Ebeling T, Jaatinen P, Laine H, Nuutila P, Salmela P, Salmi J, Stenman UH, Viikari J, Voutilainen E. A nationwide survey of mortality in acromegaly. Journal of Clinical Endocrinology and Metabolism. 2005;90:4081–4086.
    1. Ayuk J, Clayton RN, Holder G, Sheppard MC, Stewart PM, Bates AS. Growth hormone and pituitary radiotherapy, but not serum insulin-like growth factor-I concentrations, predict excess mortality in patients with acromegaly. Journal of Clinical Endocrinology and Metabolism. 2004;89:1613–1617.
    1. Bonapart IE, van Domburg R, ten Have SM, de Herder WW, Erdman RA, Janssen JA, van der Lely AJ. The ‘bio-assay’ quality of life might be a better marker of disease activity in acromegalic patients than serum total IGF-I concentrations. European Journal of Endocrinology. 2005;152:217–224.
    1. Wass JA. Growth hormone, insulin-like growth factor-I and its binding proteins in the follow-up of acromegaly. Journal of Endocrinology. 1997;155(Suppl. 1):17–19.
    1. Freda PU, Post KD, Powell JS, Wardlow SL. Evaluation of disease status with sensitive measures of growth hormone secretion in 60 postoperative patients with acromegaly. Journal of Clinical Endocrinology and Metabolism. 1998;83:3808–3816.
    1. Trainer PJ. Editorial: acromegaly – consensus, what consensus? Journal of Clinical Endocrinology and Metabolism. 2002;87:3534–3536.
    1. Biermasz NR, Pereira AM, Frölich M, Romijin JA, Veldhuis JD, Roelfsema F. Octreotide represses secretory-burst mass and nonpulsatile secretion but does not restore event frequency or orderly GH secretion in acromegaly. American Journal of Physiology – Endocrinology and Metabolism. 2004;286:25–30.
    1. Grottoli S, Celleno R, Gasco V, Pivonello R, Caramella D, Barreca A, Ragazzoni F, Pigliaru F, Alberti D, Ferrara R, Angeletti G. Efficacy and safety of 48 weeks of treatment with octreotide LAR in newly diagnosed acromegalic patients with macroadenomas: an open-label, multicenter, non-comparative study. Journal of Endocrinological Investigation. 2005;28:978–983.
    1. Murray RD, Kim K, Ren SG, Chelly M, Umehara Y, Melmed S. Central and peripheral actions of somatostatin on the growth hormone–IGF-I axis. Journal of Clinical Investigation. 2004;114:349–356.
    1. Hofland LJ, Lamberts SW. The pathophysiological consequences of somatostatin receptor internalization and resistance. Endocrine Reviews. 2003;24:28–47.
    1. James RA, Gilroy T. Dose and frequency titration of somatostatin analogues in the treatment of acromegaly – an injection of expediency. Clinical Endocrinology. 2001;54:11–13.
    1. Jenkins PJ, Akker S, Chew SL, Besser GM, Monson JP, Grossman AB. Optimal dosage interval for depot somatostatin analogue therapy in acromegaly requires individual titration. Clinical Endocrinology. 2000;53:719–724.
    1. Lucas T, Astorga R. Efficacy of lanreotide Autogel administered every 4–8 weeks in patients with acromegaly previously responsive to lanreotide microparticles, 30 mg: a phase III trial. Clinical Endocrinology. 2006;65:320–326.
    1. Ronchi CL, Boschetti M, Degli Uberti EC, Mariotti S, Grottoli S, Loli P, Lombardi G, Tamburrano G, Arvigo M, Angeletti G, Boscani PF, Beck-Peccoz P, Arosio M. Efficacy of a slow-release formulation of lanreotide (Autogel) 120 mg in patients with acromegaly previously treated with octreotide long acting release (LAR): an open, multicentre longitudinal study. Clinical Endocrinology. 2007;67:512–519.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner